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RISS 인기검색어
- 검색키워드
- 저자 : Stallcup, William (검색결과 6 건)
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Jeong, Kwang Won,Andreu-Vieyra, Claudia,You, Jueng Soo,Jones, Peter A.,Stallcup, Michael R. Oxford University Press 2014 Nucleic acids research Vol.42 No.4
<P>A number of genome-wide analyses have revealed that estrogen receptor α binding to and regulation of its target genes correlate with binding of FOXA1, a pioneer factor, to nearby DNA sites in MCF-7 breast cancer cells. The enhancer element-specific histone H3K4me1/2 mark is enriched at the specific FOXA1/ERα recruitment sites in chromatin, but the mechanism by which these enhancer marks are established in chromatin before hormone treatment is unclear. Here, we show that mixed-lineage leukemia 1 (MLL1) protein is a key determinant that maintains permissive chromatin structure of the <I>TFF1</I> enhancer region. MLL1 occupies the <I>TFF1</I> enhancer region and methylates H3K4 before hormone stimulation. <I>In vitro</I>, MLL1 binds directly to the CpG-rich region of the <I>TFF1</I> enhancer, and its binding is dependent on hypomethylation of DNA. Furthermore, the depletion of MLL1 in MCF-7 cells results in a dramatic decrease of chromatin accessibility and recruitment of FOXA1 and ERα to the enhancer element. Our study defines the mechanism by which MLL1 nucleates histone H3K4 methylation marks in CpG-enriched regions to maintain permissive chromatin architecture and allow FOXA1 and estrogen receptor α binding to transcriptional regulatory sites in breast cancer cells.</P>
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Ji Yu, Eun,Kim, Seok-Hyung,Heo, Kyu,Ou, Chen-Yin,Stallcup, Michael R.,Kim, Jeong Hoon Oxford University Press 2011 Nucleic acids research Vol.39 No.16
<P>Estrogen receptor α (ERα) plays critical roles in development and progression of breast cancer. Because ERα activity is strictly dependent upon the interaction with coregulators, coregulators are also believed to contribute to breast tumorigenesis. Cell Cycle and Apoptosis Regulator 1 (CCAR1) is an important co-activator for estrogen-induced gene expression and estrogen-dependent growth of breast cancer cells. Here, we identified Deleted in Breast Cancer 1 (DBC1) as a CCAR1 binding protein. DBC1 was recently shown to function as a negative regulator of the NAD-dependent protein deacetylase SIRT1. DBC1 associates directly with ERα and cooperates synergistically with CCAR1 to enhance ERα function. DBC1 is required for estrogen-induced expression of a subset of ERα target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ERα to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ERα and of SIRT1-mediated deacetylation of ERα. SIRT1 also represses the co-activator synergy between DBC1 and CCAR1 by binding to DBC1 and disrupting its interaction with CCAR1. Our results indicate that DBC1 and SIRT1 play reciprocal roles as major regulators of ERα activity, by regulating DNA binding by ERα and by regulating co-activator synergy.</P>
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Positive regulation of β-catenin–PROX1 signaling axis by DBC1 in colon cancer progression
Yu, E J,Kim, S-H,Kim, H J,Heo, K,Ou, C-Y,Stallcup, M R,Kim, J H Nature Publishing Group 2016 Oncogene Vol.35 No.26
<P>Aberrant activation of Wnt/beta-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the beta-catenin activity in cancer progression. Here we investigated the role of DBC1, which was recently reported as a negative regulator of SIRT1 and a transcriptional coactivator, in the regulation of Wnt/beta-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of beta-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1-beta-catenin interaction by inhibiting SIRT1-mediated beta-catenin deacetylation, thereby enhancing LEF1-beta-catenin complex formation and long-range chromatin looping at the PROX1 locus. Furthermore, DBC1 is also required for the transcriptional activity of PROX1, suggesting that DBC1 has a dual function in regulating beta-catenin-PROX1 signaling axis: as a coactivator for both beta-catenin and PROX1. Importantly, loss of DBC1 inhibited growth and tumorigenic potential of colon cancer cells, and DBC1 expression correlated with shorter relapse-free survival in patients with advanced CRC. Our results firmly establish DBC1 as a critical positive regulator of beta-catenin-PROX1 signaling axis and a key factor in beta-catenin-PROX1-mediated CRC progression.</P>
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Jin, Ming Li,Kim, Young Woong,Jin, Hong Lan,Kang, Hoin,Lee, Eun Kyung,Stallcup, Michael R.,Jeong, Kwang Won Alan R. Liss, Inc 2018 International journal of cancer Vol.143 No.11
<P>The histone H3 lysine 4‐specific methyltransferase SETD1A is associated with transcription activation and is considered a key epigenetic regulator that modulates the cell cycle and metastasis in triple‐negative breast cancer cells. However, the clinical role of SETD1A in estrogen receptor (ER)‐positive breast cancer cells remains unclear. Here, we examined whether SETD1A is a potential target for ERα‐positive breast cancer therapy. SETD1A expression was upregulated in breast tumor tissue compared to that in normal breast tissue. Moreover, ER‐target genes regulated by SETD1A were particularly enriched in cell cycle and cancer pathways. SETD1A is involved in histone H3K4 methylation, subsequent recruitment of ERα, and the establishment of accessible chromatin structure at the enhancer region of ERα target genes. In addition to ERα target genes, other cell survival genes were also downregulated by SETD1A depletion in MCF‐7 cells, leading to significant decrease in cell proliferation and migration, and spontaneous induction of apoptosis. We also found that <I>miR‐1915‐3p</I> functioned as a novel regulator of SETD1A expression in breast cells. Importantly, the growth of tamoxifen‐resistant MCF‐7 cells was effectively repressed by SETD1A knockdown. These results indicate that SETD1A may serve as a molecular target and prognostic indicator in ERα‐positive breast cancer.</P>
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SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis
Yu, E J,Kim, S-H,Kim, M J,Seo, W-Y,Song, K-A,Kang, M-S,Yang, C K,Stallcup, M R,Kim, J H Macmillan Publishers Limited 2013 Oncogene Vol.32 No.35
Estrogen receptor α (ERα) has critical roles in the development and progression of breast cancer, and the coiled-coil co-activator (CoCoA) is an important ERα co-activator for estrogen-induced gene expression. The small ubiquitin-like modifier (SUMO) pathway is hyperactivated in breast cancer, but the mechanism by which SUMOylation regulates ERα-mediated transcription remains poorly understood. Here, we identified ZFP282 as a CoCoA-binding protein. ZFP282 associates directly with ERα and cooperates synergistically with CoCoA to enhance ERα function. ZFP282 is required for estrogen-induced expression of ERα target genes and estrogen-dependent breast cancer cell growth and tumorigenesis. In addition, we found that ZFP282 is SUMOylated and that SUMOylation positively regulates the co-activator activity of ZFP282 by increasing its binding affinity to ERα and CoCoA, and consequently increasing recruitment of ZFP282–CoCoA complex to the promoter of ERα target genes. These findings reveal essential roles for ZFP282 and its SUMOylation in estrogen signaling and breast tumorigenesis.
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